Definition

	Blood absolute eosinophil count (/mm3)
Normal healthy patient-------	<500 (often <5% of leukocytes)
Eosinophilia	>500
Mild	>500-1500
Hypereosinophilia	>1500
Moderate	>1500-5000
Severe (or Massive)	>5000

"Persistent" eosinophilia is blood eosinophilia on 2 occasions, at least one month apart
Blood eosinophil count 1500 cells/mm3 (>1.5 x 10^9 cells/L) is classically considered the level above which organ damage is more likely to occur
- Note that tissue eosinophilia with potential for organ damage may be present with a normal blood eosinophil count, and vice versa
- Eosinophil count may be suppressed (masked) by endogenous (e.g. cortisol stress response to infection) or exogenous corticosteroids
Eosinophilia ≥4% is a minor criterion in the asthma predictive index
Tissue hypereosinophilia
- Can occur in the absence of blood hyperosinophilia, although in most instances at least blood eosinophilia is present
- Defined by presence of 1 or more of the following:
  - Percentage of eosinophils exceeds 20% of all nucleated cells in BM sections
  - A pathologist is of the opinion that tissue infiltration by eosinophils is extensive (massive) when compared with the normal physiologic range, compared with other inflammatory cells, or both
  - A specific stain directed against an established eosinophil granule protein (eg, major basic protein) reveals extensive extracellular deposition of eosinophil-derived proteins indicative of local eosinophil activation
  - Tissue HE can occur in the absence of blood HE, although in most instances blood HE, or at least eosinophilia, is also present.

Secondary Causes of Blood Eosinophilia

Category	Specific Conditions and Comments
Allergic Disorders	Asthma, allergic rhinitis, NARES, atopic dermatitis Often associated with only mild-moderate eosinophilia Eosinophilia >1500 is rare in these atopic conditions, more likely to be seen with ABPA or Churg-Strauss syndrome
Drug hypersensitivity	May present as isolated eosinophilia, and patient may have been on drug for years Commonly implicated drugs (overall): anticonvulsants, semisynthetic penicillins, allopurinol DRESS syndrome (Drug Rash, Eosinophilia, and Systemic Symptoms) - may include maculopapular rash, fever, atypical lymphocytosis and/or hepatitis, and can progress to renal/liver failure Triggered by anticonvulsants, sulfonamides, NSAIDs, allopurinol, abacavir, nevirapine, minocyclione, dapsone, etc; may be associated with HHV6 infection/reactivation Treatment: stop medication, start glucocorticosteroids AERD Asymptomatic eosinophilia may occur with quinine, penicillins, cephalosporins, quinolones Drug-induced eosinophils may primarily affect specific organs, e.g.: Pneumonia - associated with NSAIDs, nitrofurantoin, semisynthetic penicillins, sulfas. Blood eosinophilia may be absent. Pneumotox.com database - drugs reported to cause pulmonary infiltrates and eosinophilia Interstitial nephritis - associated with cephalosporins, semisynthetic PCNs, NSAIDs, cimetidine, sulfonamides, captopril, allopurinol, diphenylhydantoin, rifampin, ciprofloxacin, aztreonam, triazolam, and coumadin. Eosinophilia common in the involved kidneys, urine, blood eosinophilia can be absent. Hepatitis - associated with DRESS (above), semisynthetic penicillins, tetracyclines, trisalicylate, halothane, methoxyflurane, salicylazosulfapyridine, ranitidine, carbamazepine, phenytoin, and sulfa antibiotics Hypersensitivity vasculitis - allopurinol, phenytoin Gastroenterocolitis - NSAIDs Eosinophilic necrotizing myocarditis - ranitidine Angioedema - GM-CSF, IL-2
Parasites	Helminthic parasites - may initially present as blood eosinophilia (see table below) Ectoparasites - scabies, myiasis (infestation with fly larvae) Protozoa - except for Dientamoeba fragilis and Isospora belli, all other protozoa (including Giardia lamblia and Entamoeba histolytica) do not cause blood eosinophilia Rarely, infection with Sarcocystis hominis may cause eosinophilic myositis that is accompanied by blood eosinophilia CDC parasites index for specific diagnosis/treatment details
Bacteria	Bacterial infection generally causes eosinopenia with the following exceptions: Resolving scarlet fever Chronic TB
Fungal	ABPA Coccidiomycosis (valley fever) - typically eosinophilic pneumonia or cutaneous infection endemic in parts of US (AZ, CA, NV, NM, TX, UT) and Mexico, organisms may be absent from sputum cultures and lung biopsy specimens
Viral	Viral infection generally causes eosinopenia with the following exceptions: HIV - associated with advanced infection, eosinophilic folliculitis, drug hypersensitivity, and/or hypoadrenalism (due to CMV or other infections)
Neoplasm	Myeloid neoplasms Mast cell neoplasms (mastocytosis) - blood eosinophilia occurs in 25% with systemic mast cell disease Lymphoid neoplasms Paraneoplastic conditions Solid tumors/malignancy Lymphoproliferative neoplasms
Autoimmune and other diseases with immunodysregulation	Connective tissue disorders: SLE, RA, etc. Churg-Strauss syndrome Sarcoidosis Inflammatory bowel disease Autoimmune lymphoproliferative syndrome GVHD Psoriasis - associated with low-grade eosinophilia and should not be considered a sufficient explanation for blood eosinophil >1500
Primary immunodeficiency	Hyper IgE syndromes Omenn syndrome IPEX syndrome Zap70 deficiency Comel-Netherton syndrome
Other	Hypoadrenalism - associated with low-grade eosinophilia and should not be considered a sufficient explanation for blood eosinophil >1500 May result from adrenal hemorrhage, hypopituitarism, Addison disease Radiation exposure - eosinophilic, polymorphic, and pruritic eruption associated with radiotherapy (EPPER) is characterized by tumor-associated blood eosinophilia and a cutaneous eosinophilic infiltrate Cholesterol embolization Eosinophilia myalgia syndrome - associated with the ingestion of contaminated L-tryptophan (contaminant is unknown) Gleich syndrome - cyclical eosinophilia and urticaria and angioedema of the face, neck and extremities, and less often the trunk (see below) Idiopathic/HEus (hypereosinophilia of unknown significance) - a small number of patients with persistent peripheral eosinophilia (AEC > 1500/mL) for at least 5 years appear to have clinically benign disease without treatment

Helminth Parasites Causing Significant Blood Eosinophilia

Parasitic disease	Reported in US?	Notes
Angiostrongyliasis (Angiostrongylus costaricensis, cantonensis)	Yes	Infection by eating raw or undercooked snails or slugs, raw produce that contains a small snail or slug, or infected paratenic animals (crabs, freshwater shrimps) A. cantonensis most common cause of human eosinophilic meningitis A. costaricensis causes eosinophilic gastroenteritis
Ascariasis (Ascaris lumbricoides)	Yes	Infection by ingestion of eggs in soil or on unwashed produce Blood and pulmonary eosinophilia with infiltrates during early transpulmonary larval migration (Loffler's syndrome), often absent when mature
Hookworm infection Ancylostoma duodenale Necator americanus	Yes	Infection by skin contact with infected soil Blood eosinophilia during early transpulmonary larval migration, often absent when mature Common cause of low-grade eosinophilia, infection may persist years
Strongyloidiasis (Strongyloides stercoralis)	Yes	Infection by skin contact with infected soil Self-perpetuating auto-infection cycle that may persist for >50 years with variable blood eosinophilia Corticosteroids during active infection may cause hyperinfection syndrome resulting in respiratory failure
Trichinellosis (Trichinella spiralis )	Yes	Infection usually by ingestion of raw or undercooked meat (pork, bear, walrus, fox, rat, horse, and lion)
Visceral larva migrans: Toxocara canis (most common) Toxocara cati Other: Baylisascaris procyonis, Capillaria hepatica, Ascaris suum, some Ancylostoma	Yes	Primarily seen in children Infection by ingestion of dirt containing eggs shed in dog or cat feces
Gnathostomiasis (larva migrans profundus) Gnathostoma spinigerum and hispidum	No (reported in Mexico)	Infection by ingestion of raw or undercooked fresh water fish, poultry, frogs Infection/eosinophilia may persist years
Filariasis Tropical pulmonary eosinophilia (Wuchereria bancrofti or Brugia malayi) Loiasis (Loa loa) Onchocerciasis (Onchocerca volvulus) Mansonelliasis (Mansonella spp)	No	Transmitted by infected flying insect bites Infection/eosinophilia may persist years
Flukes Schistosomiasis (Schistosoma mansoni, S. haematobium, or S. japonicum) Fascioliasis (Fasciola gigantica and hepatica) Clonorchiasis (Clonorchis sinensis) Paragonimiasis (Pargonimus spp) Fasciolopsiasis (Fasciolopsis buski)	Schistosoma - No Fasciola - Yes, rare Clonorchis - No Paragonimus - Yes Fasciolopsiasis - No	Route of infection varies, typically by contact of skin with contaminated water (e.g., during swimming) or ingestion of food associated with water (fresh water fish, water plants, crustaceans) Typically blood eosinophilia during early infection Infection/eosinophilia may persist for decades with variable eosinophilia
Cysticercosis (Taenia solium)	Yes	Infection by ingestion of food/water contaminated with eggs, or secondary infection after acquiring pork tapeworm and infecting self with eggs Infection/eosinophilia may persist years
Echinococcosis (Echinococcus granulosus and multiocularis)	Yes (rare)	Infection by ingestion of soil, water, or food contaminated by the fecal matter of an infected dog, or close contact with the hair of an infected dog May remain asymptomatic until hydatid cysts grow; rupture may result in anaphylaxis Infection/eosinophilia may persist years

Diagnostic Evaluation

Must address 2 questions:
1. Is hypereosinophilia secondary to a common and treatable underlying condition? (see above)
2. Is hypereosinophilia in itself causing rapidly progressive damage?
Discontinue all suspicious drugs possible, including OTC/herbal supplements ("withdraw any agent that is not crucial for the patient’s well-being")
Evaluate/treat parasitic infections:
- Detailed travel/parasite exposure history
- CBC/diff, peripheral smear (obtained at night for microfilariae)
- Stool O+P (daily x 3), but may miss Strongyloides, Schistosoma, Trichinella, Filariae, Toxocara
- Obtain serology, most commonly:
  - Anti-Strongyloides IgG
  - Anti-Toxocara IgG
  - Anti-Schistosoma IgG
  - Anti-Ascaris lumbricoides IgG
  - Anti-Trichinella spiralis IgG
  - Antifilarial IgG4
- Scabies skin scraping
- Consider empiric anthelmintic (e.g. albendazole, or ivermectin 200 mg/Kg/day x 2 days) before starting extensive evaluation for hypereosinophilic syndrome in patients with a history of exposure to parasites, especially if treatment with steroids is anticipated
- Check CDC parasites index for parasite-specific diagnosis/treatment details
Beyond the above, a minimum standard for all patients should include:
- CBC/differential, peripheral smear looking for dysplastic eosinophils or blasts or possibly evidence of parasitic infection
- Routine chemistries, LFTs
- HIV serology
- Serum IgE
- B12 level
- Tryptase level
- ANCA
- EKG, echocardiogram, troponin, maybe cardiac MRI
  - ICON 2012: a thorough cardiac evaluation is mandatory in all patients with hypereosinophilia. Cardiac MRI is helpful in distinguishing eosinophilic cardiac disease from that of other etiologies.
- Pulmonary function test
- CT chest and abdomen
- Bone marrow aspirate and biopsy
Additional procedures and diagnostic biopsies should be guided by clinical symptoms (e.g. biopsy of esophagus)

Evalution for Eosinophilia Secondary to Mastocytosis (Weller)

Hypereosinophilic Syndrome (HES) Evaluation

Definition

Myeloproliferative variant HES (MHES)

F/P-positive MHES

*Clinically-defined MHES

CEL---

Presence of FIP1L1/PDGFRa (Fip-1-like 1/platelet derived growth factor receptor alpha, or F/P) tyrosine kinase fusion protein (resulting from a deletion in chromosome 4), identified by FISH and RT-PCR of peripheral blood or bone marrow (order both FISH and PCR)
- FIPL1-PDGFRa Assays.pdf
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Eosinophil clonality by HUMARA analysis, karyotype, or other modality
Treatment
- Typically steroid-refractory, but are very responsive to imatinib (tyrosine-kinase inhibitor) at a starting dose of 100-400 mg/d, depending on the severity of complications
- If there is evidence of cardiac involvement, corticosteroids should be administered concomitantly with imatinib to prevent acute myocarditis

Note

Much less commonly, translocation lead to PDGFRb and FGFR1 forms of MHES

Blood eosinophilia ≥1500/mm3 and ≥4 of the following
- Dysplastic eosinophils on peripheral smear
- Serum B12 level >1000 pg/mL
- Serum tryptase level >12 ng/mL
- Anemia and/or thrombocytopenia
- Hepatosplenomegaly
- Bone marrow cellularity >80%
- Spindle-shaped mast cells
- Myelofibrosis
Many respond to imatinib, typically steroid refractory

Typically steroid-refractory, but responsive to imatinib

Lymphocytic variant HES (LHES)

The mechanism of eosinophilia in this variant is thought to be the production of eosinophilopoietic cytokines (particularly IL-5) by clonal populations of phenotypically abnormal, activated T lymphocytes
Definitive
- Phenotypically aberrant T-cell population in peripheral blood detected by flow cytometry
  - Antibodies specific for the following markers should be included if routine phenotyping is normal and the lymphoproliferative variant is suspected: CD2, CD5, CD6, CD7, CD8, CD25, CD27, CD45RO, TCRα/β, TCRγ/δ, HLA-DR and CD95
- Clonal T-cell rearrangement pattern by PCR
- Increased T-cell production of eosinophilopoietic cytokines (particularly IL-5)
Supportive
- Increased serum TARC (T-cell activation-regulated chemokine)
- Increased serum IgE
- Predominantly cutaneous manifestations
- History of atopy
- Steroid-responsive
Serum IL-5 levels is not helpful as they may be normal or elevated in these patients
May progress to T-cell llymphoma
Steroids are first-line treatment

Episodic angioedema (Gleich syndrome)

Patients with this condition may develop detectable T cell clones suggesting that this disease falls under LHES
Features
- Cyclical (non-allergic) urticaria and angioedema of the face, neck and extremities, and less often the trunk
- Weight gain, with weight loss due to diuresis after steroid treatment
- Fever
- Eosinophilia with infiltration and degranulation in dermis
- Elevated IgM during a flare
- Elevated serum IL-5 precedes episode
Useful to measure eos counts q3 days for several weeks off therapy since the periodicity can be missed in the setting of intermittent steroid treatment or if counts are only obtained when symptoms present

Diagnostic algorithm for MHES and LHES

Note

MHES and LHES represent 25-33% of those with HES
In the majority of patients with HES, the cause is unknown

Summary Management Algorithm (Weller)

Treatment

Treatment varies with underlying cause of eosinophilia (see above)
- Eosinophil lowering agents other than steroids include hydroxyurea, IFN-alpha, mepolizumab (anti-IL-5 antibody)
If evidence of organ damage (particularly myocardial damage, pulmonary involvement with hypoxia, and neurological involvement) during initial evaluation, consider rapid eosinophil lowering with prednisone 1 mg/Kg daily, followed by 15 mg/Kg IV x 3 days in the absence of a response to initial PO therapy
- Ensure blood/bone marrow for HES evaluation obtained prior to rapid eosinophil lowering with steroid